Low-Dose Aspirin Added 8 Percent to Male Mouse Lifespan. In 19,114 Healthy Older Adults, It Added No Healthy Years and Deaths Ran Higher.
Does low-dose aspirin help longevity? In mice, a little. In healthy older people, the best trial says no. The National Institute on Aging's Interventions Testing Program reported in 2008 that aspirin extended median lifespan in male mice by 8 percent and did nothing for females. Ten years later the ASPREE trial gave 100 mg of aspirin or placebo to 19,114 healthy adults aged 70 and older and stopped early, at a median of 4.7 years, because aspirin was not going to add disability-free years. Deaths from any cause ran higher on aspirin, mostly from cancer. Aspirin is one of the few longevity candidates with a large human trial that measured what longevity people actually care about: staying alive and independent. That makes it a useful test case for every compound that looks good in mice. This article walks through the mouse data, the three ASPREE papers, the follow-up analyses on cancer, dementia and disability, and the current US guidance. It is educational, not medical advice. Anyone already taking aspirin for a diagnosed heart condition should not stop without talking to their doctor.
Key Takeaways: Low-Dose Aspirin and Longevity
In the NIA Interventions Testing Program, aspirin given in food from 4 months of age raised median lifespan in male mice to 849 days, an 8 percent increase, and had no effect in females (Strong and colleagues, Aging Cell, 2008). The ASPREE trial randomized 19,114 healthy adults aged 70 or older (65 or older for Black and Hispanic Americans) to 100 mg of aspirin or placebo. Disability-free survival was 21.5 versus 21.2 events per 1,000 person-years, a hazard ratio of 1.01 (McNeil and colleagues, NEJM, 2018). Death from any cause in ASPREE was 12.7 per 1,000 person-years on aspirin and 11.1 on placebo, a hazard ratio of 1.14. Cancer was the main contributor. The authors called the finding unexpected and urged caution in reading it. Major hemorrhage in ASPREE rose from 2.8 percent on placebo to 3.8 percent on aspirin, a hazard ratio of 1.38. Cardiovascular disease did not fall significantly. The US Preventive Services Task Force, in 2022, recommends against starting low-dose aspirin for primary prevention of cardiovascular disease in adults 60 or older.
Does low-dose aspirin extend lifespan?
Low-dose aspirin has extended lifespan only in male mice, and it has not extended healthy life in the one large human trial built to test it. The two results do not contradict each other so much as answer different questions in different animals. The mouse finding came from the Interventions Testing Program, a National Institute on Aging project that tests candidate drugs in genetically mixed mice at three sites: The Jackson Laboratory, the University of Michigan and the University of Texas Health Science Center at San Antonio. The human finding came from ASPREE (Aspirin in Reducing Events in the Elderly), which enrolled participants in Australia and the United States from 2010 through 2014. Only ASPREE measured an outcome that matters to a person deciding whether to take a pill: years lived alive, free of dementia and free of persistent physical disability. On that outcome, aspirin and placebo finished level.
ASPREE: Events per 1,000 Person-Years
19,114 healthy adults aged 70 or older, 100 mg aspirin or placebo, median 4.7 years. Source: McNeil and colleagues, New England Journal of Medicine, 2018 (three ASPREE papers).
- Aspirin 100 mg
- Placebo
What did the mouse study actually find?
The 2008 Interventions Testing Program study found that aspirin lengthened the lives of male mice but not female mice. Pooling all three sites, the log-rank test for males reached p=0.01. Median male lifespan on aspirin was 849 days, an 8 percent increase, according to the full paper by Strong and colleagues in Aging Cell. Two details limit the result. First, aspirin did not move the surrogate for maximum lifespan, the share of mice still alive at the age of 90 percent mortality (p=0.16). It shifted the middle of the survival curve, not its tail. Second, the study was designed to detect a 10 percent lifespan difference with 80 percent power, and the 8 percent male gain sits under that line. The authors suggested the absent effect in females could reflect sex differences in how the mice absorbed or broke down aspirin and its metabolite, salicylic acid. That pattern of a male-only effect recurs across this program. Our articles on acarbose (epithalon.com/blog/acarbose-male-lifespan-itp-human-evidence) and 17-alpha estradiol (epithalon.com/blog/17-alpha-estradiol-male-lifespan-testes-evidence) cover two other drugs with the same split.
What was the ASPREE trial?
ASPREE was a double-blind, placebo-controlled trial of daily 100 mg enteric-coated aspirin in 19,114 community-dwelling older adults with no cardiovascular disease, dementia or physical disability. Participants were 70 or older, or 65 or older for Black and Hispanic participants in the US. The median age was 74 and 56.4 percent were women. Of the 19,114 people, 9,525 received aspirin and 9,589 received placebo. The primary endpoint was a composite of death, dementia or persistent physical disability, which is a reasonable working definition of losing healthy lifespan. The trial was stopped at a median of 4.7 years of follow-up after the investigators determined that continuing would not show a benefit on that endpoint. Adherence in the final year was 62.1 percent on aspirin and 64.1 percent on placebo, which means a meaningful share of each group had stopped taking their pills by the end.
Did aspirin add healthy years in ASPREE?
Aspirin did not add healthy years in ASPREE. The rate of death, dementia or persistent physical disability was 21.5 events per 1,000 person-years on aspirin and 21.2 on placebo, a hazard ratio of 1.01 with a 95 percent confidence interval of 0.92 to 1.11, reported by McNeil and colleagues in the New England Journal of Medicine in 2018. A hazard ratio of 1.01 means the two groups lost healthy life at almost exactly the same rate. The confidence interval is narrow enough to rule out any large benefit over five years. The individual pieces of the composite told the same story. A separate ASPREE analysis by Ryan and colleagues in Neurology in 2020 counted 575 adjudicated dementia cases and found no meaningful difference in dementia triggers (hazard ratio 1.03), probable Alzheimer disease (0.96) or mild cognitive impairment (1.12). Cognitive change over time was similar in both groups.
Hazard Ratios Across ASPREE Outcomes
Aspirin versus placebo; 1.0 means no difference, above 1 favours placebo. Sources: McNeil and colleagues, NEJM 2018; Ryan and colleagues, Neurology 2020; Woods and colleagues, Journals of Gerontology 2021.
Why did more people die on aspirin?
More people died on aspirin in ASPREE mainly because of cancer. Across 1,052 deaths, the rate of death from any cause was 12.7 per 1,000 person-years on aspirin and 11.1 on placebo, a hazard ratio of 1.14 (95 percent confidence interval 1.01 to 1.29). Cancer accounted for 1.6 excess deaths per 1,000 person-years, and cancer death occurred in 3.1 percent of the aspirin group versus 2.3 percent of the placebo group. The investigators themselves flagged this result. In the NEJM mortality paper they wrote that, in the context of previous studies, it was unexpected and should be interpreted with caution. Death from any cause was a secondary endpoint, and the cause-of-death analyses were post hoc. The caution matters because earlier randomized trials, mostly in younger people, had suggested aspirin delivers a delayed cancer benefit. ASPREE does not overturn that work. It shows that in people starting aspirin at 70 or older, over about five years, no such benefit appeared and the signal ran the other way.
Does aspirin cause cancer in older adults?
ASPREE found that aspirin did not increase the number of cancers in older adults, but it was linked to cancers being more advanced. In the detailed 2021 analysis in the Journal of the National Cancer Institute, there were 981 cancer events on aspirin and 952 on placebo, a hazard ratio of 1.04 for all new cancers, which was not statistically significant. The difference appeared at later stages. Aspirin was associated with a higher risk of cancer that had already metastasized at diagnosis (hazard ratio 1.19) or was stage 4 at diagnosis (1.22), and with a higher risk of death from cancers that presented at stage 3 (2.11) or stage 4 (1.31). The authors' reading is that in older people aspirin may accelerate the progression of cancer rather than start it. That is a hypothesis drawn from secondary analyses, not a proven mechanism. It is still the strongest reason the trial's authors give for caution with aspirin in this age group.
Aspirin Did Not Raise Cancer Rates. It Tracked With Later-Stage Cancer.
Hazard ratios, aspirin versus placebo, in ASPREE (981 versus 952 cancer events). Source: McNeil and colleagues, Journal of the National Cancer Institute, 2021.
Does aspirin prevent heart attacks in healthy people?
Aspirin prevents a small number of first cardiovascular events in healthy people and causes a similar number of major bleeds. In ASPREE, cardiovascular disease ran at 10.7 per 1,000 person-years on aspirin and 11.3 on placebo, a hazard ratio of 0.95 that was not statistically significant. Major hemorrhage ran at 8.6 versus 6.2 per 1,000 person-years, a hazard ratio of 1.38. A wider view comes from a 2019 JAMA meta-analysis by Zheng and Roddick of 13 trials and 164,225 people without cardiovascular disease, median age 62. Aspirin lowered the composite of cardiovascular death, heart attack and stroke from 61.4 to 57.1 events per 10,000 participant-years (hazard ratio 0.89). Major bleeding rose from 16.4 to 23.1 per 10,000 participant-years (hazard ratio 1.43). In absolute terms, the meta-analysis put the number needed to treat to prevent one cardiovascular event at 265, and the number needed to harm to cause one major bleed at 210.
Across 13 Trials: Fewer Heart Events, More Bleeds
Events per 10,000 participant-years in 164,225 people without cardiovascular disease. Source: Zheng and Roddick, JAMA, 2019 (meta-analysis).
- Aspirin
- No aspirin
Did aspirin help anything in ASPREE?
One secondary ASPREE analysis found a small reduction in persistent disability with daily activities, though not in new disability. Woods and colleagues, writing in the Journals of Gerontology in 2021, tracked six basic activities of daily living, such as bathing and dressing, every 6 months. New disability was similar: 776 of 9,525 people on aspirin and 787 of 9,589 on placebo. Persistent disability was lower on aspirin, 4.3 versus 5.3 events per 1,000 person-years, a hazard ratio of 0.81 with a confidence interval of 0.66 to 1.00, which touches the line of no effect. Only 24 percent of new disability went on to become persistent. This is the most favourable aspirin finding in the trial and it is borderline. It did not translate into better disability-free survival, the outcome the trial was built to measure.
Who should consider low-dose aspirin today?
Under current US guidance, low-dose aspirin for primary prevention is a narrow, individual decision for some adults aged 40 to 59 and not recommended for those starting at 60 or older. The US Preventive Services Task Force, in its 2022 statement in JAMA, recommends against initiating low-dose aspirin for primary prevention of cardiovascular disease in adults 60 or older (a D recommendation). For adults aged 40 to 59 with a 10 percent or greater 10-year cardiovascular risk, the Task Force says the decision should be individual and that the net benefit is small (a C recommendation). People not at increased bleeding risk and willing to take aspirin daily are more likely to benefit. None of this applies to secondary prevention, meaning people who already have heart disease or have had a heart attack or stroke. Those patients are outside the populations studied here and should follow their own cardiologist's advice.
The Bleed Arrives Sooner Than the Benefit
Number needed to treat and number needed to harm for aspirin in primary prevention. Source: Zheng and Roddick, JAMA, 2019.
What does aspirin teach about longevity drugs tested in mice?
Aspirin shows that a lifespan gain in mice, even from a rigorous multi-site program, does not predict extra healthy years in people. The Interventions Testing Program result reached significance only when data from all three sites were pooled, came from a single 2008 cohort and was limited to males. The human trial was large, randomized and blinded, and it found no gain in disability-free survival. Several things can break the chain from mouse to human. The mice started treatment young and stayed on it for life, while ASPREE participants started at a median age of 74. The mouse effect was confined to one sex. And the endpoint differed: median lifespan in a lab colony is not the same as dementia-free, disability-free years in a free-living population. The same gap applies to metformin (epithalon.com/blog/metformin-longevity-exercise-blunting-tame-evidence), rapamycin and most compounds on the longevity shelf. Aspirin is unusual only in that the human trial was finished. Most of the others have not been tested that way yet.
Where do the figures in this article come from?
Every figure in this article comes from a source checked during research. Mouse lifespan: Strong and colleagues, Aging Cell, 2008 (doi.org/10.1111/j.1474-9726.2008.00414.x). ASPREE primary endpoint: McNeil and colleagues, New England Journal of Medicine, 2018 (doi.org/10.1056/NEJMoa1800722). ASPREE mortality: McNeil and colleagues, NEJM, 2018 (doi.org/10.1056/NEJMoa1803955). ASPREE cardiovascular events and bleeding: McNeil and colleagues, NEJM, 2018 (doi.org/10.1056/NEJMoa1805819). ASPREE cancer: McNeil and colleagues, Journal of the National Cancer Institute, 2021 (doi.org/10.1093/jnci/djaa114). ASPREE dementia: Ryan and colleagues, Neurology, 2020 (doi.org/10.1212/WNL.0000000000009277). ASPREE disability: Woods and colleagues, Journals of Gerontology Series A, 2021 (doi.org/10.1093/gerona/glaa316). Meta-analysis: Zheng and Roddick, JAMA, 2019 (doi.org/10.1001/jama.2018.20578). Guidance: US Preventive Services Task Force, JAMA, 2022 (doi.org/10.1001/jama.2022.4983).
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